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别愁 发表于 2016-7-4 13:00 
回复 StephenW 的帖子
"The antiviral efficacy of ETV is not influenced by previous treatment LAM wit ...
Discussion
We have demonstrated for the first time, the efficacy of long-term ETV treatment in Chinese NA-experienced CHB patients. Previous treatment of LAM with/without LAM-resistance does not influence the efficacy of ETV treatment. Furthermore, ETV may still be an option in ADV-experienced patients with a partial VR, but is not advised in patients with a primary treatment failure to ADV therapy. LAM and ADV are still wildly used for treatment of CHB in the developing countries. Our current findings on LAM and ADV in relation to ETV treatment may provide guideline in clinical intervention.
ETV has probably superior virologic, biochemical, and histological efficacy compared to other current NAs agents, arguably equal efficacy with tenofovir disoproxil fumarate (TDF)14. The five-year ETV clinical trial (ETV-022) demonstrated that 94% had HBV DNA < 300 copies/mL, 80% had normal ALT levels, and 23% achieved HBeAg seroconversion in NA-naïve CHB patients in Europe15. In addition, >90% ETV treated NA-naïve Chinese CHB patients achieved HBV DNA undetectable after 2 years, VP increased at 12 and 24 weeks, and HBeAg seroconversion achieved 15.4% at year three9. The above findings9,15,16 support our current study, which demonstrated that all NA-naïve patients achieved VR at year five without genotypic ETV-resistance. HBV DNA was reduced substantially accompanied by increased VR at 12 and 24 weeks, in addition to increased rate of ALT normalization. Moreover, our data also showed that the rate of HBeAg seroconversion in the Chinese patients was 17%, 28% or 33% at year two, three or five, respectively, which are similar with the results of previous studies17. The combined data from our study and previous studies demonstrate that ETV is highly effective in NA-naïve patients. It has been reported that ETV has rare occurrence of resistance in NA-naïve patients9, which is consistent with our findings over a five-year period. Thus detecting mutations for pre-existing resistance to ETV in NA-naïve patients is of limited significance from financial and practical point of view.
LAM has been routinely used as a first-line therapy for CHB patients, however has incurred major limitations due to growing resistance over the past decade18. Resistance is usually associated with a rebound in viral load and often associated with exacerbation of hepatitis19. Increasing number of treatment failure to different NA-treatment regimens poses a growing problem in daily clinical practice.
The effect of ETV monotherapy in CHB patients has been categorized into two groups: NA-naïve and NA-experienced in Reijnders’s study12. The presence of LAM-resistant mutations at the start of ETV was significantly associated with a reduced probability of achieving VR compared to LAM-naïve patients. Previous LAM treatment without development of LAM-resistance, or with a prior history of LAM-resistance, did not influence the antiviral response over a one-year period12. This data is consistent with our five-year study, demonstrating antiviral efficacy was not decreased by previous LAM treatment, with or without LAM-resistance. It was reported that ETV resistance developed more frequently in LAM-treated CHB patient over an 18-month period, but no prior history of LAM-resistance did not affect the development of ETV resistance20. Our data showed that among nine developed ETV resistance patients, three did not have LAM-resistance, but four had a prior history of LAM-resistance. Of those four patients, three subjects expressed detectable LAM-resistant mutations at the initiation of ETV monotherapy. Our five-year study suggested that LAM-resistant CHB patients with ETV treatment results in a high probability of progression to ETV-resistance, particularly in the group with previous detectable LAM-resistant mutation at the start of ETV therapy.
ADV, an established medication for the treatment of CHB, has been widely used in China in the past decade. ADV has additionally been associated with a high rate of primary treatment failure, defined as less than a 2-log reduction in viral load after six months of therapy, and a high rate of antiviral resistance2,21,22. The efficacy of ETV in CHB patients previously treated with ADV has been relatively un-studied, particularly in cases with primary treatment failure23,24. It has been also reported that the effects of ETV monotherapy in previous ADV-treated CHB patients demonstrating that partial responders do not display as good effect as ADV-complete responders25,26. Interestingly, previous treatment with ADV and presence of ADV-resistant mutations does not influence the potency of ETV12. Our five-year-period study established that there was almost equal effect with ETV treatment between the CHB patients prior to ADV therapy with a partial virology response and NA-naïve patients. Such discrepancies may be due to a difference in time period (three vs five years) and also in different populations (Caucasians vs Chinese). More importantly, we found that CHB patients with a primary treatment failure history had a reduced probability of achieving VR compared to NA-naïve patients. Therefore, the response to prior treatment is necessary for ADV-experienced patients before starting ETV monotherapy.
In our current study, all ADV-experienced and NA-naïve patients were treated with 0.5 mg ETV; whereas all LAM-experienced patients were treated with 1 mg ETV monotherapy, while NA-naïve patients were treated with 0.5 mg ETV. This data suggests that 1 mg of ETV provides no more obvious anti-viral benefit in LAM-experienced patients compared to that of NA-naïve patients with 0.5 mg ETV treatment. During the follow up, there was no significantly different follow-up time between LAM-experienced and naïve groups, however a significant difference was detected between ADV-experienced and naïve groups. As those non-VR patients had already experienced viral breakthrough within three years, the extended follow-up period may not contribute to the major cause of reduced VR among NA-experienced patients. In this study, no significant difference was observed between cirrhotic and chronic hepatitis patients, however this is more likely due to a relatively small number of patients. A large cohort study is currently being investigated.
Limitations of our study include the heterogeneous group and relative small sample size. Cox regression has been applied to correct for confounders as treatment duration, HBV DNA, HBeAg status. Nevertheless, the Out-patient Department of Infectious Diseases in Shanghai Ruijin Hospital with consultation number is 12000 per month, one of the biggest in the China, and covers large areas of patients. Thus, the patients still represent of clinical practice and make it possible to compare different groups of NA-experienced patients. We appreciate the small scale of the study, despite spanning a five-year period. A large scale study with an expanded population size, and extended period of time is currently in the process of being investigated.
Despite the influence of previous IFN exposure on the efficacy of ETV, only 17 (19%) of patients had prior experience of IFN treatment within our current study. The impact of IFN to long-term ETV therapy is currently lacking in understanding, and still requires further exploration.
In conclusion, ETV proved to be efficacious in NA-naïve patients. ETV may still be an option in ADV-experienced patients with a partial virology response, however it is not recommended in patients with a primary treatment failure to ADV therapy.
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楼主: StephenW
发表于 2016-7-4 14:13
